Genomic DNA Insertions and Deletions Occur Frequently Between Humans and Nonhuman Primates

Numerous comparative sequence studies have demonstrated that there is more similarity at the nucleotide level between humans and chimpanzees than between humans and any other species (King and Wilson 1975; Hacia 2001). Thus, identifying the types and extent of DNA sequence variation existing between humans and chimpanzees will be important for understanding the genetic basis of recently evolved, human-specific traits (Gagneux and Varki 2001). Previous comparative studies, focused on analyzing the differences between aligned human and chimpanzee sequences (single-nucleotide fixed differences), have indicated that the two species are 98.4%–98.8% identical at the nucleotide level (Koop et al. 1989; Chen and Li 2001; Fujiyama et al. 2002). The ∼1.5% single-nucleotide fixed differences have, to date, been the primary focus of studies aimed at understanding the biological differences, resulting from qualitative and quantitative differential gene expression, between humans and chimpanzees. It was demonstrated previously that large-scale segmental duplications (>400 kb; Bailey et al. 2002), pericentric inversions (Nickerson and Nelson 1998), and chromosomal fusions (Yunis and Prakash 1982) occurring after the separation of humans and chimpanzees from their common evolutionary ancestor resulted in DNA differences between the two species. Several human–chimpanzee comparative sequence analyses have suggested that smaller-sized rearrangements may also exist between human and chimpanzee DNA (Ueda et al. 1990; Fujiyama et al. 2002). However, the extent and significance of DNA sequence differences between humans and chimpanzees due to these smaller-sized genomic rearrangements are poorly characterized. Furthermore, the size, chromosomal distribution across gene-rich and gene-poor intervals, and evolutionary history of these genomic rearrangements have not yet been systematically examined. We recently demonstrated that human high-density oligonucleotide arrays provide a rapid and effective tool for comparing human sequences with the DNA of other mammalian species (Frazer et al. 2001). We previously performed a cross-species comparative sequence analysis of human chromosome 21 by hybridizing mouse and dog bacterial artificial chromosome (BAC) DNA to human 21q arrays in order to identify evolutionarily conserved elements. In this report we describe the use of human high-density arrays for large-scale comparisons of human sequences with those of nonhuman primates to identify genomic rearrangements that result in DNA sequence differences between the species.